Targeted therapies, including vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib (first line therapy), and mTOR inhibitors such as temsirolimus and everolimus (second line therapy), are standard of care in treating advanced renal cell carcinoma (RCC; 1-4). Temsirolimus and everolimus are rapamycin analogs (rapalogs) that inhibit the mammalian target of rapamycin complex 1 (mTORC1)5-7. International phase HI trials led to their approval for treating kidney cancer, yet only demonstrated modest clinical benefit with median progression free survival (PFS) of 4.9-5.5 months (8-11).
However, extended periods of freedom from disease progression with rapalogs have been reported in isolated patients among whom some were refractory to first line antiangiogenic agents (10,12,13). These clinical data raise a testable hypothesis that genomic alterations may dictate clinical response.
Hyperactive PI3K/AKT/mTOR signaling, through its effects on protein synthesis, cell survival, and metabolism, has long been implicated in promoting tumor growth. The serine-threonine kinase mTOR exerts its actions as the enzymatic component of two structurally and functionally distinct multi-protein complexes, mTORC1 and mTORC2 (6,7). Therapeutic inhibition of mTORC1 is the mechanism of action for rapalogs. Components of the PI3K/mTOR pathway can either act as activators (PI3K, AKT, and Rheb) or repressors (PTEN, TSC1, and TSC2) of the mTORC1 signaling (14). Functional loss of TSC1 and TSC2 was shown in preclinical models to sensitize tumors to rapalogs (15), and everolimus has been approved for treating subependymal giant-cell astrocytomas and angiomyolipoma in patients with Tuberous Sclerosis Complex (16,17). Recent reports have also implicated TSC1 as a tumor suppressor in RCC and bladder cancer patients (18,19). However, the recent elucidation of intra-tumor heterogeneity of kidney cancer challenges the predictability of genomic biomarkers derived from single biopsies (20).